Abstract
Overproduction of reactive oxygen species (ROS) is known to mediate glutamate excitotoxicity in neurological diseases. However, how ROS burdens can influence neural circuit integrity remains unclear. Here, we investigate the impact of excitotoxicity induced by depletion of Drosophila Eaat1, an astrocytic glutamate transporter, on locomotor central pattern generator (CPG) activity, neuromuscular junction architecture, and motor function. We show that glutamate excitotoxicity triggers a circuit-dependent ROS feedback loop to sculpt the motor system. Excitotoxicity initially elevates ROS, thereby inactivating cholinergic interneurons and consequently changing CPG output activity to overexcite motor neurons and muscles. Remarkably, tonic motor neuron stimulation boosts muscular ROS, gradually dampening muscle contractility to feedback-enhance ROS accumulation in the CPG circuit and subsequently exacerbate circuit dysfunction. Ultimately, excess premotor excitation of motor neurons promotes ROS-activated stress signaling that alters neuromuscular junction architecture. Collectively, our results reveal that excitotoxicity-induced ROS can perturb motor system integrity through a circuit-dependent mechanism.
Highlights
Reactive oxygen species (ROS) are generated as the by-product of mitochondrial oxidative phosphorylation (Adam-Vizi, 2005)
We identified a hypomorphic mutation of Drosophila excitatory amino acid transporter 1
The mutant allele contained an insertion of a roo transposon in the last intron of the eaat1 locus, which results in a severe reduction of Eaat1 protein levels (Figure 1—figure supplement 1A–D)
Summary
Reactive oxygen species (ROS) are generated as the by-product of mitochondrial oxidative phosphorylation (Adam-Vizi, 2005). In the central nervous system, under physiological conditions, high energy demand results in higher levels of ROS production relative to those in other body parts. Endogenously generated ROS were recognized as signaling molecules that regulate a range of nervous system processes, including neuronal polarity, growth cone pathfinding, neuronal development, synaptic plasticity, and neural circuit tuning (Li et al, 2016; Oswald et al, 2018a; Oswald et al, 2018b). ROS overproduction and/or overwhelming the antioxidant machinery can generate ROS burdens, termed oxidative stress, in aging and diverse pathological conditions (Blesa et al, 2015; Bozzo et al, 2017; Liguori et al, 2018; Pollari et al, 2014; Wang et al, 2014; Zhao and Zhao, 2013). Advancing our understanding of the mechanisms underlying ROS-induced neurotoxicity should aid the development of potent therapeutic treatments for neurological disorders
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